Phenylketonuria (PKU) is the most common inborn aminoacidopathy caused by a deficiency in phenylalanine hydroxylase, resulting in an accumulation of phenylalanine (Phe) and is converted into phenylpyruvate, also known as phenylketone. This accumulation also occurs in the brain.
The genetic mutations characteristic for Phenylketonuria (PKU) impair the proper functioning of the enzyme phenylalanine hydroxylase (PAH), which normally converts phenylalanine (Phe) to tyrosine (Tyr). This mutation causes Phe to accumulate in blood and brain to toxic levels. Additionally, as Tyr is the precursor for the neurotransmitters Dopamine and Noradrenaline, a decrease in Tyr synthesis disrupts the biosynthesis of these catecholamines. In parallel, Phe competes with Tyr and Tryptophan (Trp, the precursor for Serotonin) at amino acid transporters across the blood brain barrier (BBB) and as a consequence, the high Phe concentrations in the blood also leads to a reduced brain entry of Tyr and Trp, further impacting on their availability for neurotransmitter and protein biosynthesis in neurons.
Similarly, mutations in the co-enzyme tetrahydrobiopterin (tetrahydrobiopterin-deficiency) impair proper conversion of Phe to Tyr, resulting in Phe accumulation, or hyperphenylalaninemia. The availability of Dopamine and Serotonin is critical as these neurotransmitters are involved in a variety of functions, particularly in the Prefrontal Cortex which is the main site of higher cognitive functions. In PKU patients still on diet and with plasma Phe concentrations controlled within the recommended levels, metabolism of both Dopamine and Serotonin was proposed to be deficient, as cerebrospinal fluid measurements showed reduced levels of metabolites of these neurotransmitters. In parallel, studies involving early and continuously treated children with PKU have demonstrated deficits in executive functioning, including strategic processing, processing speed, problem solving, non-verbal intelligence, working memory and attention flexibility.
Concluding, PKU disturbs brain development and leads to progressive mental retardation and cognitive defect. Fortunately, some cognitive deficits as well as certain anatomical impairment observed in patients with PKU seem to be reversible. For instance, reaction time, a parameter for processing speed and which has been found reduced in patients with PKU, has shown reversible when off-diet PKU patients return to a protein-free diet supplemented with amino acids. Additionally, white matter deficits and more specifically myelination deficits have been associated with blood Phe levels. Similarly to the effects of re-initiated diet on cognitive functions, it has been observed with Magnetic Resonance Imaging that these myelin deficits may be partially reversed. Lili Liang et al. reported in NeuroReport 2011, 22:617-622 that PKU-related brain impairment is accompanied with abnormalities of dendritic spines and synapses in a BTBR-Pah mouse model.
Outside the field of PKU, EP2162019 discloses a composition comprising a lipid blend optionally in combination with cytidine or uridine for improving brain function in Alzheimer's disease. Synaptic dysfunction in Alzheimer's disease is closely related to beta-Amyloid toxicity, and beta-amyloid plaque deposition as cause for synaptic dysfunction and neurodegeneration. Alzheimer's disease is therefore seen as a loss of existing (functioning) synapses.
The above observations point towards a potential opportunity for an improved dietary intervention aimed at restoring neuronal and cognitive function associated with PKU which is the object of the present invention. Current low-Phe dietary treatment prevents mental retardation, but cognitive outcome remains suboptimal. Therefore a need remains to improve the nutritional treatment of PKU and PKU-related neurological damage as it is presently available in the art, and to improve nutritional treatment of PKU by improving brain functions.